SUMMARY-ABSTRACT The overall goal of this proposal is to construct two pre-cancer atlases (PCAs) from highly accessible pre- malignant diseases that impose high burdens on human health (i) one focused on progression of pre- melanoma lesions to invasive cancer and (ii) a second on progression from clonal hematopoiesis (CHIP) to myeloid neoplasms. Both of these involve expansion of specific clones in normal and diseased niches as shaped by complex interactions among immune and pre-cancer cells. The resulting Atlases developed by the Center for Pre-cancer Atlases of Cutaneous and Hematologic Origin (PATCH Center) present complementary technical challenges, avenues to scientific discovery, and opportunities for the development of precision prevention strategies and therapies. The key goal in both cases is to precisely delineate and understand the molecular mechanisms driving progression from pre-malignant to malignant disease, to identify high risk individuals, prioritize particular therapies and serve as the foundation for precision prevention clinical trials. This will be achieved by integrated characterization of single cell genotype and cell states using high-plex tissue imaging and omic characterization of cross-sectional and well-controlled longitudinal patient cohorts. Aim 1 will establish an administrative core responsible for scientific management of the Center, coordination with HTAN members and dissemination of Atlases under the direction of an internal Executive Committee with three subcommittees. Aim 2 will establish a Biospecimen Unit under the leadership of pathologists, oncologists and a surgeon. The DFCI Pasquarello Tissue Repository will provide highly annotated hematological specimens for image-based and omic characterization of CHIP; the BWH dermatopathologic tissue repository will provide annotated FFPE samples for melanoma precursors. These services will also play a key role in prospective sample acquisition and analysis. Aim 3 will establish a Characterization Unit directed by an oncologist and pathologist to perform and integrate single-cell genomics, multiplex flow cytometry and high- plex imaging using two methods reduced to practice within the Center: tissue-based cyclic immunofluorescence (t-CyCIF) and DNA exchange imaging (DEI). The Characterization Unit will also validate reagents and associate all primary results with appropriate metadata, protocols and reagent specifications. Aim 4 will establish a Data Analysis Unit enlisting systems and computational biologists and data scientists to manage all aspects of data acquisition, interpretation and visualization. This is expected to be the most technically challenging aspect of the Atlas projects. The Data Analysis Unit will release Phase I/II atlases each in preliminary and final stages to facilitate collaborative and crowd-sourced approaches to algorithm development. The resulting human browsable and machine-readable atlases are expected to yield new scientific discoveries, demonstrate the feasibility and utility of new technologies and help to reduce the incidence of life-threatening cancers of the skin and blood.